Sodium-dependent glucose transporter 2 inhibitors effects on myocardial function in patients with type 2 diabetes and asymptomatic heart failure

BACKGROUND Sodium-dependent glucose transporter 2 inhibitors(SGLT2i)have shown efficacy in reducing heart failure(HF)burden in a very heterogeneous groups of patients,raising doubts about some contemporary assumptions of their mechanism of action.We previously published a prospective observational study that evaluated mechanisms of action of SGLT2i in patients with type 2 diabetes who were in HF stages A and B on dual hypoglycemic therapy.Two groups of patients were included in the study:the ones receiving SGLT2i as an add-on agent to metformin and the others on dipeptidyl peptidase-4 inhibitors as an add-on to metformin due to suboptimal glycemic control.AIM To evaluate the outcomes regarding natriuretic peptide,oxidative stress,inflammation,blood pressure,heart rate,cardiac function,and body weight.METHODS The study outcomes were examined by dividing each treatment arm into two subgroups according to baseline parameters of global longitudinal strain(GLS),N-terminal pro-brain natriuretic peptide,myeloperoxidase(MPO),high-sensitivity C-reactive protein(hsCRP),and systolic and diastolic blood pressure.To evaluate the possible predictors of observed changes in the SGLT2i arm during follow-up,a rise in stroke volume index,body mass index(BMI)decrease,and lack of heart rate increase,linear regression analysis was performed.RESULTS There was a greater reduction of MPO,hsCRP,GLS,and blood pressure in the groups with higher baseline values of mentioned parameters irrespective of the therapeutic arm after 6 months of follow-up.Significant independent predictors of heart rate decrease were a reduction in early mitral inflow velocity to early diastolic mitral annular velocity at the interventricular septal annulus ratio and BMI,while the predictor of stroke volume index increase was SGLT2i therapy itself.CONCLUSION SGLT2i affect body composition,reduce cardiac load,improve diastolic/systolic function,and attenuate the sympathetic response.Glycemic control contributes to the improvement of heart function,blood pressure control,oxidative stress,and reduction in inflammation.

Effects of sodium-dependent glucose transporter 2 inhibitors in patients with type 2 diabetes mellitus and asymptomatic heart failure

Sodium-dependent glucose transporter 2 inhibitors(SGLT2i)have been increa-singly used with proven efficacy in patients with heart failure(HF),regardless of diabetes status.GrubićRotkvićet al recently published an observational study on SGLT2i therapy in patients with type 2 diabetes mellitus and asymptomatic HF.They found that the use of SGLT2i led to reduced cardiac load and improved cardiovascular performance,reinforcing the evolving paradigm that SGLT2i are not merely glucose-lowering agents but are integral to the broader management of cardiovascular risk in patients with type 2 diabetes mellitus.The study by GrubićRotkvićet al contributes to the growing body of literature supporting the early use of SGLT2i in patients with diabetic cardiomyopathy,offering a potential strategy to mitigate the progression of HF.Future larger studies should be con-ducted to confirm these findings,and explore the long-term cardiovascular bene-fits of SGLT2i,particularly in asymptomatic patients at risk of developing HF.

Effects of octreotide on glucose transporter type 2expression in obese rat small intestine

AIM： TO investigate the effects of the somatostatin analogue, octreotide, on maltose and sucrase activities and expression of glucose transporter type 2 （GLUT2） in obese rat intestinal mucosa. METHODS： We divided 49 Sprague-Dawley rats into a group of 31 high fat diet-induced obese rats and a group of 18 normal controls. The obese rats were separated into an octreotide treated group 9f 16 rats and an obese group of 15. The intervention （：jroup was injected with octreotide at 40 ±g/kg body weight every 12 h for 8 d. Rat body weight was measured weekly to calculate Lee＇s index. After euthanization, maltase and sucrase activities in the small intestine were measured by activity assays, and the fasting plasma glucose level was measured. The expression of GLUT2 in small intestinal mucosa was analyzed by immunohistochemistry, reverse transcriptase polymerase chain reaction and Western blotting assays. RESULTS： Body weight, Lee＇s index, fasting plasma glucose level, maltase activity in small intestinal mucosa, mucosa and apical GLUT2, GLUT2 mRNA and protein expression levels were all significantly higher in the obese group than in the normal control group （605.61 ± 141.00 vs 378.54 ±111.75, 337.61 ± 10.82 vs 318.73 ± 20.10, 8.60± 1.38 vs 7.33 ± 0.70, 156.01 ± 58.81 vs 50.43 ± 30.49, 390 744.2± 62 469.21 vs 170 546.50 ± 50 646.14, 26 740.18 ±3809.60 vs 354.98± 57.19, 0.26± 0.11 vs 0.07± 0.02, and 2.08 ± 0.59 vs 1.27 ± 0.38, respectively, all P 〈 0.01）. Sucrase activity did not differ between the two groups. Octreotide intervention significantly decreased the body weight and fasting plasma glucose level of obese rats （508.27 ± 94.39 vs 605.61 ± 141.00, 7.58 ± 1.51 vs 8.60±1.38, respectively, all P 〈 0.05）. The intestinal mucosa and apical GLUT2, expression of GLUT2 mRNA and protein were also significantly lower in the octreotide intervention group than in the obese group （269 975.2 ± 53 730.94 vs 390 744.2 ± 62 469.21, 3758.06 ± 364.51 vs 26 740.18 ± 3809.60, 0.08 ± 0.02 vs 0.26 ±0.11, and 1.31 ± 0.27 vs 2.08 ±0.59, respectively, all P 〈 0.01）. CONCLUSION： High fat dietinduced obesity is associated with elevated intestinal maltase activity, GLUT2 expression, and permanent apical GLUT2 in the small intestinal mucosa of rats. Octreotide can inhibit these effects.

SGLT2 inhibitors in the prevention of diabetic cardiomyopathy:Targeting the silent threat

Heart failure(HF)is a major global health challenge,particularly among indi-viduals with type 2 diabetes mellitus(T2DM),who are at significantly higher risk of developing HF.Diabetic cardiomyopathy,a unique form of heart disease,often progresses silently until advanced stages.Recent research has focused on sodium-dependent glucose transporter 2 inhibitors(SGLT2i),originally developed for hyperglycemia,which have shown potential in reducing cardiovascular risks,including HF hospitalizations,irrespective of diabetic status.In this editorial we comment on the article by GrubićRotkvićet al published in the recent issue of the World Journal of Cardiology.The investigators examined the effects of SGLT2i on myocardial function in T2DM patients with asymptomatic HF,finding significant improvements in stroke volume index and reductions in systemic vascular resis-tance,suggesting enhanced cardiac output.Additionally,SGLT2i demonstrated anti-inflammatory and antioxidant effects,as well as blood pressure reduction,though the study’s limitations—such as small sample size and observational design—necessitate larger randomized trials to confirm these findings.The study underscores the potential of early intervention with SGLT2i in preventing HF progression in T2DM patients.

Sodium-dependent glucose transporter 2 inhibitors:Transforming diabetic cardiomyopathy management

This article addresses the substantial findings of a study on sodium-dependent glucose transporter 2 inhibitors(SGLT2is)and their effects on myocardial function in patients with type 2 diabetes and asymptomatic heart failure.The editorial explores the broader implications of the study findings for clinical practice,thus highlighting the pivotal role of SGLT2is in improving cardiac function,reducing oxidative stress,and attenuating inflammation.It emphasizes the importance of early intervention with SGLT2is in preventing the progression of diabetic cardio-myopathy;hence,these inhibitors have the potential to transform the manage-ment of asymptomatic heart failure in patients with diabetes.

Fanconi-Bickel syndrome in an infant with cytomegalovirus infection: A case report and review of the literature

BACKGROUND Fanconi–Bickel syndrome(FBS)is a rare autosomal recessive disorder caused by mutation of the SLC2A2 gene,which encodes glucose transporter protein 2(GLUT2).CASE SUMMARY We report a 7-mo-old girl with cytomegalovirus infection presenting hepatomegaly,jaundice,liver transaminase elevation,fasting hypoglycemia,hyperglycosuria,proteinuria,hypophosphatemia,rickets,and growth retardation.After prescription of ganciclovir,the levels of bilirubin and alanine aminotransferase decreased to normal,while she still had aggravating hepatomegaly and severe hyperglycosuria.Then,whole exome sequencing was conducted and revealed a homozygous c.416delC mutation in exon 4 of SLC2A2 inherited from her parents,which was predicted to change alanine 139 to valine(p.A139Vfs*3),indicating a diagnosis of FBS.During the follow-up,the entire laboratory test returned to normal with extra supplement of vitamin D and corn starch.Her weight increased to normal range at 3 years old without hepatomegaly.However,she still had short stature.Although there was heterogeneity between phenotype and genotype,Chinese children had typical clinical manifestations.No hot spot mutation or association between severity and mutations was found,but nonsense and missense mutations were more common.Data of long-term follow-up were rare,leading to insufficient assessment of the prognosis in Chinese children.CONCLUSION FBS is a rare genetic metabolic disease causing impaired glucose liver homeostasis and proximal renal tubular dysfunction.Results of urine and blood testing suggesting abnormal glucose metabolism could be the clues for FBS in neonates and infants.Genetic sequencing is indispensable for diagnosis.Since the diversity of disease severity,early identification and long-term follow-up could help improve patients’quality of life and decrease mortality.

Overview of Type 2 Diabetes Drugs on the Market

Type 2 Diabetes Mellitus (T2DM) is a systemic metabolic disorder with complex pathogenesis. In recent years, a variety of new T2DM drugs have emerged, such as sodium-dependent glucose transporters 2 (SGLT-2) inhibitors, glucagon-like peptide-1 (GLP-1) receptor agonists and dipeptidyl peptidase-4 (DPP-4) inhibitors. As traditional medicines, insulin also has developed kinds of formulations such as quick-acting or premixed insulin. In addition, new treatment schedules combining multiple drugs are also fully explored. The efficacy, the administration, the mechanism, the safety and the price of these drugs are all different, providing patients with multiple options. This paper reviews the main types of type 2 diabetes drugs on the market and describes the mechanism of action. The representative type 2 diabetes treatment drugs are listed, and the advantages and disadvantages of these representative drugs are preliminarily evaluated. This information is reviewed to help doctors with clinical medication.

PXR activation impairs hepatic glucose metabolism partly via inhibiting the HNF4α-GLUT2 pathway

Drug-induced hyperglycemia/diabetes is a global issue. Some drugs induce hyperglycemia by activating the pregnane X receptor(PXR), but the mechanism is unclear. Here, we report that PXR activation induces hyperglycemia by impairing hepatic glucose metabolism due to inhibition of the hepatocyte nuclear factor 4-alpha(HNF4 a)-glucose transporter 2(GLUT2) pathway. The PXR agonists atorvastatin and rifampicin significantly downregulated GLUT2 and HNF4 a expression, and impaired glucose uptake and utilization in HepG2 cells. Overexpression of PXR downregulated GLUT2 and HNF4 a expression, while silencing PXR upregulated HNF4 a and GLUT2 expression.Silencing HNF4 a decreased GLUT2 expression, while overexpressing HNF4 a increased GLUT2 expression and glucose uptake. Silencing PXR or overexpressing HNF4 a reversed the atorvastatininduced decrease in GLUT2 expression and glucose uptake. In human primary hepatocytes, atorvastatin downregulated GLUT2 and HNF4 a mRNA expression, which could be attenuated by silencing PXR. Silencing HNF4 a downregulated GLUT2 mRNA expression. These findings were reproduced with mouse primary hepatocytes. Hnf4 a plasmid increased Slc2 a2 promoter activity. Hnf4 a silencing or pregnenolone-16 a-carbonitrile(PCN) suppressed the Slc2 a2 promoter activity by decreasing HNF4 a recruitment to the Slc2 a2 promoter. Liver-specific Hnf4 a deletion and PCN impaired glucose tolerance and hepatic glucose uptake, and decreased the expression of hepatic HNF4 a and GLUT2. In conclusion, PXR activation impaired hepatic glucose metabolism partly by inhibiting the HNF4 aGLUT2 pathway. These results highlight the molecular mechanisms by which PXR activators induce hyperglycemia/diabetes.

GLUCOSE TRANSPORTER 2: PREVENTION OF STREPTOZOTOCIN-INDUCED REDUCTION OF 5-THIO-D-GLUCOSE

Decreased expression of glucose transporter 2 (GLUT2) has been found to correlate with impaired secreting β-cell function in diabetes. Here, the aim was to study if the GLUT2 of pancreatic islets is a target structure for streptozotocin (STZ) in vitro. GLLT2 expression was determined by Western blot analysis, using lysates prepared from islets of C57BL / 6mice. A dose-dependent decrement of GLUT2 expression was found after incubation of islets with streptozotocin for 30 min. Compared with solvent-incubated islets, a subtoxic dose (4mM) of STZ resulted in a reduction of approximate 58% of GLUT2 expression and a toxic dose